Skip to main content

Advertisement

Log in

The role of transforming growth factor beta in thyroid autoimmunity: current knowledge and future perspectives

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

A Correction to this article was published on 02 June 2022

This article has been updated

Abstract

The complex mechanisms, which are related to the pathophysiology and the development of autoimmune thyroid diseases, involve transforming growth factor beta (TGF-β) and its interplay with the immune system. The aim of this review is to examine the role of TGF-β regarding thyroid autoimmunity and explore the potent role of this molecule either as a diagnostic or prognostic marker or a therapeutic target regarding autoimmune thyroid diseases. TGF-β is clearly a master regulator of the immune response, exerting either inhibitory or facilitatory effects on cells of the immune system. Thus, this molecule is involved in the pathogenesis and development of autoimmune thyroid diseases. Recent research has revealed the involvement of TGF-β in the pathophysiology of autoimmune thyroid diseases. The role of TGF-β in the development of autoimmune thyroid diseases varies, depending on its concentrations, the type of the activated TGF-β signalling pathway, the genetic predisposition of the patient and the pathophysiologic stage of the disease. TGF-β could emerge as a useful diagnostic or prognostic marker for the evolution of thyroid autoimmunity. Promising perspectives for the effective therapeutic use of TGF-β regarding thyroid autoimmunity exist. The main treatment approaches incorporate either enhancement of the immunosuppressive role of TGF-β or inhibition of its facilitatory role in the autoimmune thyroid diseases. Further research towards deeper understanding of TGF-β physiology and clinical application of its possible therapeutic role regarding thyroid autoimmunity is needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Change history

References

  1. Smith TJ, Hegedus L. Graves’ disease. N Engl J Med. 2016;375(16):1552–65. https://doi.org/10.1056/NEJMra1510030.

    Article  PubMed  Google Scholar 

  2. Li Q, Wang B, Mu K, Zhang J-A. The pathogenesis of thyroid autoimmune diseases: new T lymphocytes—cytokines circuits beyond the Th1−Th2 paradigm. J Cell Physiol. 2018. https://doi.org/10.1002/jcp.27180.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Antonelli A, et al. Graves’ disease: clinical manifestations, immune pathogenesis (cytokines and chemokines) and therapy. Best Pract Res Clin Endocrinol Metab. 2020;34(1): 101388. https://doi.org/10.1016/j.beem.2020.101388.

    Article  CAS  PubMed  Google Scholar 

  4. Papanastasiou L, et al. Thyroid autoimmunity in the current iodine environment. Thyroid. 2007;17(8):729–39. https://doi.org/10.1089/thy.2006.0299.

    Article  CAS  PubMed  Google Scholar 

  5. Mitsiades N, et al. Fas/Fas ligand up-regulation and Bcl-2 down-regulation may be significant in the pathogenesis of Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 1998;83(6):2199–203. https://doi.org/10.1210/jcem.83.6.4853.

    Article  CAS  PubMed  Google Scholar 

  6. Lee HJ, et al. Immunogenetics of autoimmune thyroid diseases: a comprehensive review. J Autoimmun. 2015;64:82–90. https://doi.org/10.1016/j.jaut.2015.07.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ragusa F, et al. Hashimotos’ thyroiditis: epidemiology, pathogenesis, clinic and therapy. Best Pract Res Clin Endocrinol Metab. 2019;33(6):101367. https://doi.org/10.1016/j.beem.2019.101367.

    Article  PubMed  Google Scholar 

  8. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726–38. https://doi.org/10.1056/NEJMra0905750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci. 2014;55(3):1735–48. https://doi.org/10.1167/iovs.14-14002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Turck N, et al. Thyroid-associated orbitopathy and biomarkers: where we are and what we can hope for the future. Dis Markers. 2018;2018:7010196. https://doi.org/10.1155/2018/7010196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Diana T, Ponto KA, Kahaly GJ. Thyrotropin receptor antibodies and Graves’ orbitopathy. J Endocrinol Invest. 2020. https://doi.org/10.1007/s40618-020-01380-9.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Taylor PN, et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol. 2020;16(2):104–16. https://doi.org/10.1038/s41574-019-0305-4.

    Article  CAS  PubMed  Google Scholar 

  13. Tingi E, et al. Benign thyroid disease in pregnancy: a state of the art review. J Clin Transl Endocrinol. 2016;6:37–49. https://doi.org/10.1016/j.jcte.2016.11.001.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Vitoratos N, et al. Reproductive corticotropin-releasing hormone. Ann N Y Acad Sci. 2006;1092:310–8. https://doi.org/10.1196/annals.1365.029.

    Article  CAS  PubMed  Google Scholar 

  15. Lima J, et al. Regulatory T cells show dynamic behavior during late pregnancy, delivery, and the postpartum period. Reprod Sci. 2017;24(7):1025–32. https://doi.org/10.1177/1933719116676395.

    Article  CAS  PubMed  Google Scholar 

  16. Sakkas EG, et al. Associations of maternal oestradiol, cortisol, and TGF-beta1 plasma concentrations with thyroid autoantibodies during pregnancy and postpartum. Clin Endocrinol (Oxf). 2018;89(6):789–97. https://doi.org/10.1111/cen.13843.

    Article  CAS  Google Scholar 

  17. Nguyen CT, Mestman JH. Postpartum thyroiditis. Clin Obstet Gynecol. 2019;62(2):359–64. https://doi.org/10.1097/GRF.0000000000000430.

    Article  PubMed  Google Scholar 

  18. Di Bari F, et al. Autoimmune abnormalities of postpartum thyroid diseases. Front Endocrinol (Lausanne). 2017;8:166. https://doi.org/10.3389/fendo.2017.00166.

    Article  Google Scholar 

  19. Hinck AP, Mueller TD, Springer TA. Structural biology and evolution of the TGF-beta family. Cold Spring Harb Perspect Biol. 2016. https://doi.org/10.1101/cshperspect.a022103.

  20. Pisarev MA, Thomasz L, Juvenal GJ. Role of transforming growth factor beta in the regulation of thyroid function and growth. Thyroid. 2009;19(8):881–92. https://doi.org/10.1089/thy.2007.0303.

    Article  CAS  PubMed  Google Scholar 

  21. Massague J. TGF-beta signaling in development and disease. FEBS Lett. 2012;586(14):1833. https://doi.org/10.1016/j.febslet.2012.05.030.

    Article  CAS  PubMed  Google Scholar 

  22. Wipff PJ, Hinz B. Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship. Eur J Cell Biol. 2008;87(8–9):601–15. https://doi.org/10.1016/j.ejcb.2008.01.012.

    Article  CAS  PubMed  Google Scholar 

  23. Heldin CH, Moustakas A. Signaling receptors for TGF-beta family members. Cold Spring Harb Perspect Biol. 2016. https://doi.org/10.1101/cshperspect.a022053

  24. Ark AV, Cao J, Li X. TGF-beta receptors: in and beyond TGF-beta signaling. Cell Signal. 2018;52:112–20. https://doi.org/10.1016/j.cellsig.2018.09.002.

  25. Zandvoort A, et al. Altered expression of the Smad signalling pathway: implications for COPD pathogenesis. Eur Respir J. 2006;28(3):533–41. https://doi.org/10.1183/09031936.06.00078405.

    Article  CAS  PubMed  Google Scholar 

  26. Hata A, Chen YG. TGF-beta signaling from receptors to Smads. Cold Spring Harb Perspect Biol. 2016. https://doi.org/10.1101/cshperspect.a022061

  27. Zhang Y, Alexander PB, Wang XF. TGF-beta family signaling in the control of cell proliferation and survival. Cold Spring Harb Perspect Biol. 2017;9(4).

  28. Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19(1):128–39. https://doi.org/10.1101/cshperspect.a022145.

    Article  CAS  PubMed  Google Scholar 

  29. Turner JA, et al. Regulatory T cell-derived TGF-beta1 controls multiple checkpoints governing allergy and autoimmunity. Immunity. 2020;53(6):1331–2. https://doi.org/10.1016/j.immuni.2020.10.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Egesten A, Gordon S, Herwald H. Innate immunity - a clinical perspective. J Intern Med. 2019;285(5):477–8. https://doi.org/10.1111/joim.12898.

    Article  CAS  PubMed  Google Scholar 

  31. Kelly A, et al. Regulation of innate and adaptive immunity by TGFbeta. Adv Immunol. 2017;134:137–233. https://doi.org/10.1016/bs.ai.2017.01.001.

    Article  CAS  PubMed  Google Scholar 

  32. Gorelik L, Constant S, Flavell RA. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med. 2002;195(11):1499–505. https://doi.org/10.1084/jem.20012076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010;31(6):220–7. https://doi.org/10.1016/j.it.2010.04.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol. 2013;131(4):959–71. https://doi.org/10.1016/j.jaci.2013.01.046.

    Article  CAS  PubMed  Google Scholar 

  35. Santaguida MG, et al. BREG cells in Hashimoto’s thyroiditis isolated or associated to further organ-specific autoimmune diseases. Clin Immunol. 2017;184:42–7. https://doi.org/10.1016/j.clim.2017.04.012.

    Article  CAS  PubMed  Google Scholar 

  36. Mincione G, et al. EGF and TGF-beta1 effects on thyroid function. J Thyroid Res. 2011;2011: 431718. https://doi.org/10.4061/2011/431718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Logan A, et al. Enhanced expression of transforming growth factor-beta 1 during thyroid hyperplasia in rats. J Endocrinol. 1994;141(1):45–57.

    Article  CAS  Google Scholar 

  38. Cowin AJ, Bidey SP. Transforming growth factor-beta 1 synthesis in human follicular thyroid cells: differential effects of iodide and plasminogen on the production of latent and active peptide forms. J Endocrinol. 1994;141(1):183–90.

    Article  CAS  Google Scholar 

  39. Carneiro C, et al. TGF-beta1 actions on FRTL-5 cells provide a model for the physiological regulation of thyroid growth. Oncogene. 1998;16(11):1455–65. https://doi.org/10.1038/sj.onc.1201662.

    Article  CAS  PubMed  Google Scholar 

  40. Kang HC, et al. Pax-8 is essential for regulation of the thyroglobulin gene by transforming growth factor-beta1. Endocrinology. 2001;142(1):267–75. https://doi.org/10.1210/endo.142.1.7918.

    Article  CAS  PubMed  Google Scholar 

  41. Napolitano G, et al. Transforming growth factor-beta1 down-regulation of major histocompatibility complex class I in thyrocytes: coordinate regulation of two separate elements by thyroid-specific as well as ubiquitous transcription factors. Mol Endocrinol. 2000;14(4):486–505. https://doi.org/10.1210/mend.14.4.0454.

    Article  CAS  PubMed  Google Scholar 

  42. Martelossi Cebinelli GC, et al. TGF-beta1 functional polymorphisms: a review. Eur Cytokine Netw. 2016;27(4):81–9.

    Article  Google Scholar 

  43. Vural P, et al. Arg25Pro (c.915G>C) polymorphism of transforming growth factor beta1 gene suggests an association with increased risk for Hashimoto's thyroiditis. Int Immunopharmacol 2015;28(1):521–4. https://doi.org/10.1016/j.intimp.2015.07.019

  44. Santin AP, Furlanetto TW. Role of estrogen in thyroid function and growth regulation. J Thyroid Res. 2011;2011: 875125. https://doi.org/10.4061/2011/875125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gantus MA, et al. Estradiol modulates TGF-beta1 expression and its signaling pathway in thyroid stromal cells. Mol Cell Endocrinol. 2011;337(1–2):71–9. https://doi.org/10.1016/j.mce.2011.02.001.

    Article  CAS  PubMed  Google Scholar 

  46. Qin J, et al. Estrogen receptor beta activation stimulates the development of experimental autoimmune thyroiditis through up-regulation of Th17-type responses. Clin Immunol. 2018;190:41–52. https://doi.org/10.1016/j.clim.2018.02.006.

    Article  CAS  PubMed  Google Scholar 

  47. Ito I, et al. Estrogen inhibits transforming growth factor beta signaling by promoting Smad2/3 degradation. J Biol Chem. 2010;285(19):14747–55. https://doi.org/10.1074/jbc.M109.093039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Prud’homme GJ, Piccirillo CA. The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases. J Autoimmun. 2000;14(1):23–42. https://doi.org/10.1006/jaut.1999.0339.

    Article  CAS  PubMed  Google Scholar 

  49. McLachlan SM, et al. The link between Graves’ disease and Hashimoto’s thyroiditis: a role for regulatory T cells. Endocrinology. 2007;148(12):5724–33. https://doi.org/10.1210/en.2007-1024.

    Article  CAS  PubMed  Google Scholar 

  50. Widder J, et al. The immunoregulatory influence of transforming growth factor beta in thyroid autoimmunity: TGF beta inhibits autoreactivity in Graves’ disease. J Autoimmun. 1991;4(4):689–701. https://doi.org/10.1016/0896-8411(91)90186-g.

    Article  CAS  PubMed  Google Scholar 

  51. Kutluturk F, et al. Association of cytokine gene polymorphisms (IL6, IL10, TNF-alpha, TGF-beta and IFN-gamma) and Graves’ disease in Turkish population. Endocr Metab Immune Disord Drug Targets. 2013;13(2):163–7. https://doi.org/10.1042/BSR20180143.

    Article  CAS  PubMed  Google Scholar 

  52. Yamada H, et al. The +869T/C polymorphism in the transforming growth factor-beta1 gene is associated with the severity and intractability of autoimmune thyroid disease. Clin Exp Immunol. 2008;151(3):379–82. https://doi.org/10.1111/j.1365-2249.2007.03575.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yoshida A, Hisatome I, Taniguchi S, et al. Pendrin is a novel autoantigen recognized by patients with autoimmune thyroid diseases. J Clin Endocrinol Metab. 2009;94:442–8. https://doi.org/10.1210/jc.2008-1732.

    Article  CAS  PubMed  Google Scholar 

  54. Akinci B, et al. Hashimoto’s thyroiditis, but not treatment of hypothyroidism, is associated with altered TGF-beta1 levels. Arch Med Res. 2008;39(4):397–401. https://doi.org/10.1016/j.arcmed.2007.12.001.

    Article  CAS  PubMed  Google Scholar 

  55. Morris GP, Brown NK, Kong YC. Naturally-existing CD4(+)CD25(+)Foxp3(+) regulatory T cells are required for tolerance to experimental autoimmune thyroiditis induced by either exogenous or endogenous autoantigen. J Autoimmun. 2009;33(1):68–76. https://doi.org/10.1016/j.jaut.2009.03.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Braley-Mullen H, et al. Role of TGFbeta in development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J Immunol. 2001;167(12):7111–8.

  57. Chen K, et al. Mechanisms of spontaneous resolution versus fibrosis in granulomatous experimental autoimmune thyroiditis. J Immunol. 2003;171(11):6236–43.

    Article  CAS  Google Scholar 

  58. Chen K, et al. Characterization of thyroid fibrosis in a murine model of granulomatous experimental autoimmune thyroiditis. J Leukoc Biol. 2000;68(6):828–35.

    CAS  PubMed  Google Scholar 

  59. Lacheta D, et al. Immunological aspects of graves’ ophthalmopathy. Biomed Res Int. 2019;2019:7453260. https://doi.org/10.1155/2019/7453260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Longo CM, Higgins PJ. Molecular biomarkers of Graves’ ophthalmopathy. Exp Mol Pathol. 2019;106:1–6. https://doi.org/10.1016/j.yexmp.2018.11.004.

    Article  CAS  PubMed  Google Scholar 

  61. Khoo TK, et al. Evidence for enhanced Thy-1 (CD90) expression in OFs of patients with Graves’ ophthalmopathy. Thyroid. 2008;18(12):1291–6. https://doi.org/10.1089/thy.2008.0255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Valyasevi RW, et al. Effect of tumor necrosis factor-alpha, interferon-gamma, and transforming growth factor-beta on adipogenesis and expression of thyrotropin receptor in human orbital preadipocyte fibroblasts. J Clin Endocrinol Metab. 2001;86(2):903–8.

    CAS  PubMed  Google Scholar 

  63. Ko J, et al. Sphingosine-1-phosphate mediates fibrosis in orbital fibroblasts in graves’ orbitopathy. Invest Ophthalmol Vis Sci. 2017;58(5):2544–53. https://doi.org/10.1167/iovs.16-20684.

    Article  CAS  PubMed  Google Scholar 

  64. Fang S, et al. Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in graves orbitopathy. J Clin Endocrinol Metab. 2017;102(11):4273–83. https://doi.org/10.1210/jc.2017-0134972.

    Article  PubMed  Google Scholar 

  65. Lv LF, et al. Expression level and clinical significance of IL-2, IL-6 and TGF-beta in elderly patients with goiter and hyperthyroidism. Eur Rev Med Pharmacol Sci. 2017;21(20):4680–6.

    PubMed  Google Scholar 

  66. Seo JY, et al. Positive feedback loop between plasminogen activator inhibitor-1 and transforming growth factor-beta1 during renal fibrosis in diabetes. Am J Nephrol. 2009;30(6):481–90. https://doi.org/10.1159/000242477.

    Article  CAS  PubMed  Google Scholar 

  67. Khalilzadeh O, et al. Genetic susceptibility to Graves’ ophthalmopathy: the role of polymorphisms in anti-inflammatory cytokine genes. Ophthalmic Genet. 2010;31(4):215–20. https://doi.org/10.3109/13816810.2010.515648.

    Article  CAS  PubMed  Google Scholar 

  68. Davies TF. The thyroid immunology of the postpartum period. Thyroid. 1999;9(7):675–84. https://doi.org/10.1089/thy.1999.9.675.

    Article  CAS  PubMed  Google Scholar 

  69. Miedema A. The role of regulatory T-cells (Tregs) in pregnancy, pre-eclampsia and beyond. Essay. Master. Biomedical Sciences: Univercity of Gronigen; 2016.

    Google Scholar 

  70. Singh M, et al. Changes in maternal serum transforming growth factor beta-1 during pregnancy: a cross-sectional study. Biomed Res Int. 2013;2013: 318464. https://doi.org/10.1155/2013/31846478.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Briana DD, et al. Fetal concentrations of the growth factors TGF-alpha and TGF-beta1 in relation to normal and restricted fetal growth at term. Cytokine. 2012;60(1):157–61. https://doi.org/10.1016/j.cyto.2012.06.005.

    Article  CAS  PubMed  Google Scholar 

  72. Liakos P, et al. Transforming growth factor beta1 inhibits aldosterone and cortisol production in the human adrenocortical cell line NCI-H295R through inhibition of CYP11B1 and CYP11B2 expression. J Endocrinol. 2003;176(1):69–82.

    Article  CAS  Google Scholar 

  73. LiVolsi VA. Postpartum thyroiditis. The pathology slowly unravels. Am J Clin Pathol. 1993;100(3):193–5.

  74. Intenzo CM, et al. Clinical, laboratory, and scintigraphic manifestations of subacute and chronic thyroiditis. Clin Nucl Med. 1993;18(4):302–6. https://doi.org/10.1097/00003072-199304000-00007.

    Article  CAS  PubMed  Google Scholar 

  75. De Leo S, Pearce EN. Autoimmune thyroid disease during pregnancy. Lancet Diabetes Endocrinol. 2018;6(7):575–86. https://doi.org/10.1016/S2213-8587(17)30402-3.

    Article  PubMed  Google Scholar 

  76. Olivieri A, et al. Postpartum thyroiditis is associated with fluctuations in transforming growth factor-beta1 serum levels. J Clin Endocrinol Metab. 2003;88(3):1280–4. https://doi.org/10.1210/jc.2002-020990.

    Article  CAS  PubMed  Google Scholar 

  77. Lazarus JH, et al. Clinical aspects of recurrent postpartum thyroiditis. Br J Gen Pract. 1997;47(418):305–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Maraka S, et al. Subclinical hypothyroidism in women planning conception and during pregnancy: who should be treated and how? J Endocr Soc. 2018;2(6):533–46. https://doi.org/10.1210/js.2018-00090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Stefoni S, et al. Low TGF-beta1 serum levels are a risk factor for atherosclerosis disease in ESRD patients. Kidney Int. 2002;61(1):324–35. https://doi.org/10.1046/j.1523-1755.2002.00119.x.

    Article  CAS  PubMed  Google Scholar 

  80. Duffy SS, Keating BA, Moalem-Taylor G. Adoptive transfer of regulatory T cells as a promising immunotherapy for the treatment of multiple sclerosis. Front Neurosci. 2019;13:1107. https://doi.org/10.3389/fnins.2019.01107.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Zhou X, et al. Therapeutic potential of TGF-beta-induced CD4(+) Foxp3(+) regulatory T cells in autoimmune diseases. Autoimmunity. 2011;44(1):43–50. https://doi.org/10.3109/08916931003782163.

    Article  CAS  PubMed  Google Scholar 

  82. Chipuk JE, et al. The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3. J Biol Chem. 2002;277(2):1240–8. https://doi.org/10.1074/jbc.M108855200.

    Article  CAS  PubMed  Google Scholar 

  83. Bogdahn U, et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 2011;13(1):132–42. https://doi.org/10.1093/neuonc/noq142.

    Article  CAS  PubMed  Google Scholar 

  84. Akhurst RJ. Targeting TGF-beta signaling for therapeutic gain. Cold Spring Harb Perspect Biol. 2017. https://doi.org/10.1101/cshperspect.a022301.

  85. Cutroneo KR. Evidence for TGF-beta1 and bleomycin intracellular signaling through autocrine regulation of Smad 3 binding to the proximal promoter of the Smad 7 gene. J Cell Biochem. 2006;97(5):933–9. https://doi.org/10.1002/jcb.20594.

    Article  CAS  PubMed  Google Scholar 

  86. Azimi A. Pentoxifylline explores new horizons in treatment of Hashimoto thyroiditis. Biol Med. 2016. https://doi.org/10.4172/0974-8369.1000293.

  87. Kunzmann S, et al. Effect of progesterone on Smad signaling and TGF-beta/Smad-regulated genes in lung epithelial cells. PLoS One. 2018;13(7): e0200661. https://doi.org/10.1371/journal.pone.0200661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kuroki H, et al. Effect of LSKL peptide on thrombospondin 1-mediated transforming growth factor beta signal activation and liver regeneration after hepatectomy in an experimental model. Br J Surg. 2015;102(7):813–25. https://doi.org/10.1002/bjs.9765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hofling DB, et al. Effects of low-level laser therapy on the serum TGF-beta1 concentrations in individuals with autoimmune thyroiditis. Photomed Laser Surg. 2014;32(8):444–9. https://doi.org/10.1089/pho.2014.3716.

    Article  CAS  PubMed  Google Scholar 

  90. Gyorfi AH, Matei AE, Distler JHW. Targeting TGF-beta signaling for the treatment of fibrosis. Matrix Biol. 2018;68–69:8–27. https://doi.org/10.1016/j.matbio.2017.12.016.

    Article  CAS  PubMed  Google Scholar 

  91. Cheng AM, et al. Celecoxib and pioglitazone as potential therapeutics for regulating TGF-beta-induced hyaluronan in dysthyroid myopathy. Invest Ophthalmol Vis Sci. 2016;57(4):1951–9. https://doi.org/10.1167/iovs.15-18018.

    Article  CAS  PubMed  Google Scholar 

  92. Rouch A, et al. Small molecules inhibitors of plasminogen activator inhibitor-1 - an overview. Eur J Med Chem. 2015;92:619–36. https://doi.org/10.1016/j.ejmech.2015.01.010.

    Article  CAS  PubMed  Google Scholar 

  93. Mastorakos G, et al. T4 but not T3 administration is associated with increased recurrence of Graves’ disease after successful medical therapy. J Endocrinol Invest. 2003;26(10):979–84. https://doi.org/10.1007/BF03348195.

    Article  CAS  PubMed  Google Scholar 

  94. Alonso-Merino E, et al. Thyroid hormones inhibit TGF-beta signaling and attenuate fibrotic responses. Proc Natl Acad Sci USA. 2016;113(24):E3451–60. https://doi.org/10.1073/pnas.1506113113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Batlle E, Massague J. Transforming growth factor-beta signaling in immunity and cancer. Immunity. 2019;50(4):924–40.

    Article  CAS  Google Scholar 

  96. Huber S, Schramm C. TGF-beta and CD4+CD25+ regulatory T cells. Front Biosci. 2006;11:1014–23. https://doi.org/10.2741/1859.

    Article  CAS  PubMed  Google Scholar 

  97. Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol. 2016;16(2):102–11.

    Article  CAS  Google Scholar 

  98. Filippi CM, et al. Transforming growth factor-beta suppresses the activation of CD8+ T-cells when naive but promotes their survival and function once antigen experienced: a two-faced impact on autoimmunity. Diabetes. 2008;57(10):2684–92. https://doi.org/10.2337/db08-0609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ganeshan K, Bryce PJ. Regulatory T cells enhance mast cell production of IL-6 via surface-bound TGF-beta. J Immunol. 2012;188(2):594–603. https://doi.org/10.4049/jimmunol.1102389.

    Article  CAS  PubMed  Google Scholar 

  100. Cazac BB, Roes J. TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo. Immunity. 2000;13(4):443–51. https://doi.org/10.1016/S1074-7613(00)00044-3.

    Article  CAS  PubMed  Google Scholar 

  101. Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell. 2008;134(3):392–404. https://doi.org/10.1016/j.cell.2008.07.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Oh SA, Li MO. TGF-beta: guardian of T cell function. J Immunol. 2013;191(8):3973–9.

    Article  CAS  Google Scholar 

  103. Konkel JE, et al. Transforming growth factor-beta signaling in regulatory T cells controls T Helper-17 cells and tissue-specific immune responses. Immunity. 2017;46(4):660–74. https://doi.org/10.1016/j.immuni.2017.03.015.

    Article  CAS  PubMed  Google Scholar 

  104. Spender LC, et al. TGF-beta induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-XL. Cell Death Differ. 2009;16(4):593–602. https://doi.org/10.1038/cdd.2008.183.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was underwritten with no funding.

Author information

Authors and Affiliations

Authors

Contributions

Each author contributed substantially to the manuscript. Specifically: Idea of the article: KE and MG, Conceptualization: KE and MG; Methodology: KE and MG; Investigation: KE; Resources: KE; Writing—Original Draft Preparation: KE and MG; Writing—Review & Editing: KE, SE, RM, MD and MG; Visualization: KE, SE, RM, MD and MG; Supervision: MG; Project Administration: KE and MG. All authors have read and agreed to the final published version of the manuscript.

Corresponding author

Correspondence to George Mastorakos.

Ethics declarations

Conflict of interest

There is no potential conflict of interest for the authors and the authors have nothing to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised as the author noticed that in pubmed and in proof, the publication appears under the names and not the surnames.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kardalas, E., Sakkas, E., Ruchala, M. et al. The role of transforming growth factor beta in thyroid autoimmunity: current knowledge and future perspectives. Rev Endocr Metab Disord 23, 431–447 (2022). https://doi.org/10.1007/s11154-021-09685-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-021-09685-7

Keywords

Navigation